Levamisole treatment in steroid-sensitive and steroid-resistant nephrotic syndrome

Since 1992 we have treated 11 children with frequently relapsing steroid-sensitive (n=6) or steroid-resistant (n=5) nephrotic syndrome with levamisole. All had been non-responsive to other immunosuppressive medication before levamisole treatment. All steroid-sensitive patients had signs of steroid toxicity. At least 1 kidney biopsy had been performed prior to study in each patient. Five children had minimal glomerular changes and the other 6 focal segmental glomerular sclerosis. The patients were treated with levamisole (2.5 mg/kg per 48 h) for at least 2 months (up to 18 months, median 10 months). Two patients had additional immunosuppression (cyclosporine A) during levamisole treatment. All patients with steroid-sensitive nephrotic syndrome became free of proteinuria within 2 months and have remained in remission after discontinuation of levamisole (follow-up time 8–50 months, median 24 months). None of the children with steroid-resistant nephrotic syndrome experienced a remission. Side effects were observed in 2 patients and included a granulocytopenia and a severe psoriasis-like cutaneous reaction; both were reversible after discontinuation of levamisole. We conclude that levamisole is of benefit in steroid-sensitive nephrotic syndrome but not in steroid-resistant nephrotic syndrome. Received August 10, 1997; received in revised form February 11, 1998; accepted February 12, 1998     

HLA-DQB1 and DRB1 alleles in Egyptian children with steroid-sensitive nephrotic syndrome

Steroid-sensitive nephrotic syndrome (SSNS) of children has been associated with several HLA-DR and DQ alleles. To investigate this association in Egyptian children, 27 patients with SSNS were typed for HLA-DRB1 and DQB1 alleles using DNA polymerase chain-reverse hybridization technique. The results were compared with 121 healthy subjects for HLA-DRB1 and 59 subjects for DQB1 alleles. We found that: (1) patients have higher frequencies of both DQB1 ^* 0601 (81.5% vs. 10.2% in controls, Pc = 0.0001) and DRB1 ^* 01 (44.4% vs. 3.3% in controls, Pc = 0.00003). Their relative risks are significantly high [38.9, confidence interval (CI) = 10.7–140.7, and 23.4, CI=6.7–81.9, respectively]; (2) the frequency of DRB1 ^* 11 alleles was low in SSNS patients (3.75% vs. 32.2% in controls), but was not significant when P was corrected (P = 0.005, Pc = NS). These findings suggest that DQB1 ^* 0601 and DRB1 ^* 01 or closely associated unknown genes confer susceptibility to SSNS. However, further studies with larger numbers of patients are needed. Received June 27, 1997; received in revised form October 23, 1997; accepted October 26, 1997     

Evidence-based management of steroid-sensitive nephrotic syndrome

Using data from systematic reviews and randomised controlled trials, the evidence for managing steroid sensitive nephrotic syndrome (SSNS) is reviewed. In the initial episode, increased duration (3–7 months) of prednisone compared with 2 months significantly reduced the risk for relapse at 12–24 months [relative risk (RR) 0.70; 95% confidence intervals (CI) 0.58–0.84] without increase in adverse effects. Six months of prednisone was significantly more effective than 3 months (RR 0.57; 95% CI 0.45–0.71). Higher prednisone doses given for the same duration reduced the risk of relapse (RR 0.59; 95% CI 0.42–0.84) suggesting that both dose and duration of prednisone therapy lead to prolonged remission. In relapsing SSNS prolonged prednisone treatment, daily prednisone during infections, oral or intravenous cyclophosphamide, chlorambucil, levamisole and cyclosporin significantly reduced the risk of relapse. Comparative effects of these options remain uncertain because of the absence of head-to-head trials, but existing trial evidence is strongest for cyclophosphamide and cyclosporin. Further adequately powered multinational trials are required to determine the optimum induction dose and duration of prednisone in the initial episode of SSNS and to determine the relative efficacies of immunosuppressive agents and the efficacy of newer agents, including mycophenolate and tacrolimus, in relapsing SSNS.An erratum to this article can be found at     

Serum selenium level and glutathione peroxidase activity in steroid-sensitive nephrotic syndrome

In our previous study the pattern of glutathione peroxidase (GPX) activity in the course of steroid–sensitive nephrotic syndrome (SSNS) in children suggested a defect in antioxidant defense. In the present report the serum selenium (Se) level, an essential component of GPX activity, was measured in a comparable group of children with SSNS at the same clinical stages at which GPX activity was determined in the previous study. Nephrotic children had normal serum Se levels during the edematous stage, at the end of prednisone treatment, and in remission. At the end of high-dose prednisone treatment, the serum Se level increased (P<0.01) simultaneously with enhanced activity of GPX. These results suggest that children with SSNS have a persistent defect in the antioxidant defense at the important stage of hydrogen peroxide and fatty acid hydroperoxide decomposition. This defect is transiently alleviated by high-dose prednisone treatment.     

Long-term effects of immunosuppressants in steroid-dependent nephrotic syndrome

In order to elucidate long-term effects of immunosuppressants, we studied 60 children with steroid-dependent nephrotic syndrome who were treated with three immunosuppressants: cyclophosphamide (n=34), chlorambucil (n=11), and cyclosporin A (n=15). Each relapse before and after the administration of immunosuppressants was evaluated longitudinally in terms of the relapse-free period and the maintenance dose of prednisolone required. The median follow-up period after immunosuppressants was 5.2 years (range 0.5–20.3 years).The relapse-free period was significantly longer in all groups after the initiation of immunosuppressants. However, the relapse-free period after subsequent relapses as compared with the previous relapse was longer in the cyclophosphamide group, similar in the chlorambucil group, and shorter in the cyclosporin A group. The prednisolone dosage at relapse was reduced in subsequent relapses after cyclophosphamide and chlorambucil treatment, but tended to be higher in later relapses after the initiation of cyclosporin A. These findings suggest that the effects of cyclophosphamide are long lasting, while those of chlorambucil and cyclosporin A are of short duration. Children who relapse after cyclosporin A treatment may experience a worse relapsing course. Received September 8, 1997; received in revised form February 27, 1998; accepted March 12, 1998     

Circannual variation in the onset and relapse of steroid-sensitive nephrotic syndrome

Idiopathic nephrotic syndrome is the most common form of nephrotic syndrome in children, but little is known about the etiology of the disease. To obtain new insights into the etiology of the disease, we studied circannual patterns of initial episodes and relapses of steroid-sensitive nephrotic syndrome (SSNS). From 1986 to 2003, there were 45 children with SSNS in our hospital, and they experienced 43 relapses during that period. Initial episodes of SSNS were found to show significant circannual variation with an autumn peak both by Rogers test and Freedmans test, and the circannual pattern was more obvious in patients with high serum IgE levels. Chronological evaluation by means of Fourier analysis showed a clear circannual pattern. In contrast, relapses of SSNS showed circannual variation with a spring peak, which was a result of a high frequency of relapses after upper respiratory infections in January. These results suggest that circannual variation in initial episodes of SSNS might be associated with allergic predisposition, whereas circannual variation in relapses might be associated with preceding upper respiratory infections.     

Family structure and the course of steroid-sensitive nephrotic syndrome

The number of children in nontraditional families is growing. The objective of this study was to determine the effects of family structure on the course of childhood steroid-sensitive idiopathic nephrotic syndrome (SSNS). Sixteen children, 2–15 years of age, with SSNS were enrolled in the study. The effects of family structure (traditional versus nontraditional) on the number of hospitalizations and outpatient visits for the previous 2 years and disease relapses for the preceding year were evaluated. Behavior differences were assessed using the Child Behavior Checklist (CBCL). Of the 16 families, 9 were traditional and 7 nontraditional. Hospitalizations, outpatient visits, and behavior were not different between family groups. However, children from nontraditional homes relapsed 3 times more than children from traditional homes (P=0.003). We conclude that children with SSNS from nontraditional homes may be at risk for more relapses compared with children from traditional families. Heightened support and monitoring is necessary for these children. Received: 23 January 2001 / Revised: 20 June 2001 / Accepted: 10 July 2001     

ACE I/D gene polymorphism in primary FSGS and steroid-sensitive nephrotic syndrome

The role of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism in various renal disorders has been investigated. We evaluated the association between the clinical characteristics and ACE genotypes of Turkish children with primary focal segmental glomerulosclerosis (FSGS) and steroid-sensitive nephrotic syndrome (SSNS). Patients with FSGS (n=30) were classified into two groups: one with remission together with stable renal function (n=22) and the other without remission and with impaired renal function (n=8). We classified children with SSNS (n=43) that were followed for at least 4 years into two subgroups as having more frequent (n=19) and less frequent relapses (n=11). The DD genotype was more frequent in the SSNS group than that in controls (37% vs. 17%, ²=4.98, P=0.025). However, among SSNS subgroups, the frequency of the DD genotype was not different. The distribution of ACE genotype was similar among patients with FSGS and SSNS. There was no difference in the ACE I/D distribution between children with FSGS and normal controls (II 10%, ID 60%, DD 30% vs. II 13%, ID 70%, DD 17%). The frequency of the DD genotype was higher in FSGS patients with declining renal function (63%) than in those with stable renal function (18%) (P=0.031). Progressive renal impairment was significantly more frequent in patients with FSGS with the homozygous D allele compared with FSGS patients with ID and II genotypes. Our results indicate that the DD genotype may be a risk factor for the development of progressive renal impairment in children with FSGS; however, larger studies are required to confirm this.The abstract of this study was accepted as a poster for the 36th meeting of the European Society of Paediatric Nephrology, Bilbao, September 2002. This study was supported in part by a grant from the Istanbul University Research Fund (no T-849/17072000)     

Steroid-responsive nephrotic syndrome in a patient with nail-patella syndrome

Nail-patella syndrome (NPS) is a rare disorder with autosomal dominant mode of inheritance. We report a child with NPS and steroid-responsive, frequently relapsing nephrotic syndrome. The child had dystrophic nails, flexion contractures of both elbows and normal renal functions. X-rays of the knees and pelvis showed hypoplastic patellae and iliac horns. Renal histology was unremarkable with mild focal increase in mesangial cellularity compatible with minimal change disease. Ultrastructural features of NPS including thickening of the glomerular basement membrane with electron-lucent areas were not found.     

Influence of age at onset on the outcome of steroid-sensitive nephrotic syndrome

To investigate whether age at onset of steroid-sensitive nephrotic syndrome (SSNS) is predictive of subsequent relapses, or influences outcome, we retrospectively studied 60 patients who were under 10 years of age at onset and were followed for over 10 years. They were divided into three groups according to age at diagnosis: group 1–3 (1.0–3.9 years at onset, n=24), group 4–6 (4.0–6.9 years at onset, n=22), and group 7–9 (7.0–9.9 years at onset, n=14). In the 51 patients with long-term remission, defined as remaining relapse-free over 3 years, the total number of relapses was significantly more in group 1–3 (n=18) than in group 4–6 (n=19), and the interval between onset and long-term remission was significantly longer. Group 4–6 and group 7–9 had fewer patients with active disease at 10 years, follow-up than group 1–3, as assessed by the Kaplan-Meier method. These data suggest that the age at onset of SSNS influences the clinical course (i.e., frequency of relapses) and the time to reach long-term remission. An age of less than 4 years at onset of SSNS is associated with greater likelihood for frequent relapses and a greater time interval to attain long-term remission. Received September 12, 1997; received in revised form February 17, 1998; accepted February 19, 1998     

Major histocompatibility complex antigens in steroid-responsive nephrotic syndrome

An increased frequency of specific major histocompatibility complex (MHC) class I, II and III antigens in children with steroid-responsive nephrotic syndrome (SRNS) has been reported. This frequency distortion, in some cases, is thought to affect the outcome of the disorder. We studied the phenotypic frequency of HLA antigens-A,-B, and-DR, as well as complement proteins Bf and C4 in an unrelated population of 25 SRNS children. Complete MHC haplotypes were also derived for four families in which 8 individuals developed SRNS. HLA-DR8, with a relative risk of 4.8, showed the strongest association with SRNS. Nonetheless, the 95% confidence intervals of this and the relative risks for all other antigens fell below 1.0. No common haplotype was found in SRNS patients in whom complete family studies were available, and disease and inheritance of the MHC were discordant in two of these families. In this study of well-characterized SRNS patients we were unable to discover a clear association between this disorder and the MHC.     

Prediction of subsequent relapse in children with steroid-sensitive nephrotic syndrome

Among nephrotic children with frequent relapses at risk for cumulative steroid toxicity, identification of children who may be at high risk for subsequent relapse is very important in making the decision to introduce cytotoxic drugs. We examined the clinical course of 467 relapses in 121 steroid-sensitive nephrotic children to elucidate the risk factors for subsequent relapse, using the Cox proportional-hazards regression model. Gender, age at onset, duration of illness from onset, prednisolone dosage at the most-recent relapse, and regimens of initial steroid therapy at onset were not associated with risk. Relapse within the 1st year was a powerful independent predictor of subsequent relapse irrespective of the duration of illness. The hazard ratio of patients with more than one relapse within the 1st year increased to 1.72–2.12 compared with those without a relapse within the 1st year. The remission period just before the most-recent relapse was also a significant predictor. The risk for patients with a 1-year or longer remission period decreased to 0.57. Patients treated with cyclophosphamide for 12 weeks had a significantly longer remission than those treated with prednisolone alone. Our results suggest that early relapse after onset and/or a short remission period just before recent relapse are independent risk factors for subsequent relapse. Cytotoxic therapy has serious adverse effects and its effect may be limited. Our results may be helpful in deciding on the suitability of cytotoxic drugs. Received: 21 September 2000 / Revised: 12 June 2001 / Accepted: 14 June 2001     

T-lymphocyte activation in steroid-sensitive nephrotic syndrome in childhood

We undertook a sequential study in 29 children with steroid-sensitivenephrotic syndrome (SSNS) off treatment to seek evidence forT-cell activation in relapse. T-cell subsets and activationmarkers were analysed using two-colour flow cytometry. SolubleIL2 receptor (sIL2R) was measured in serum and urine by enzyme-linkedimmunosorbent assay (ELISA). Fifteen children were examinedin remission and subsequent relapse (group A) and fourteen remainedin remission (group B). In group A the proportion of CD4⁺ cellsexpressing the activation marker CD25 (alpha-chain of the IL2receptor) increased significantly from remission to relapse:CD4⁺25⁺ cells rose from 5.6 to 7.0% of total lymphocytes, andfrom 15.8 to 19.1% of CD4⁺ lymphocytes (paired t test: P<0.0005and <0.001 respectively). No correlations were found betweenCD4⁺25⁺ cells and plasma albumin or cholesterol concentrations.SIL2R concentration in serum did not change in relapse, butincreased significantly in urine from 272 to 592 U/mg creatinine(P<0.01). No significant difference was found in remissionbetween groups A and B. We conclude that early relapse in SSNSis associated with activation of CD4⁺ (T-helper) cells whichis not secondary due to the nephrotic state itself.     

Steroid-sensitive nephrotic syndrome in two families

Few reports of familial cases of steroid-sensitive nephrotic syndrome (SSNS) are available. Of 123 children with SSNS, four cases in two families are presented. Two sisters and a father and his daughter developed SSNS. The incidence of SSNS siblings in Japan seems to be similar to the incidence reported in other countries. SSNS in two generations is rare. To our knowledge, cases of SSNS in a parent and a child in Japan have not been reported.     

Treatment of steroid-resistant post-transplant nephrotic syndrome with cyclophosphamide in a child with congenital nephrotic syndrome

A child with congenital nephrotic syndrome underwent renal transplantation, was treated for acute rejection, and then developed nephrotic syndrome and renal failure. He was felt to have minimal change disease on allograft biopsy, but failed to respond to therapy with corticosteroids. Cyclophosphamide was substituted for cyclosporine and rapidly induced a complete remission of his nephrotic syndrome. We feel that this case not only represents an important example of a useful therapeutic approach to the child with congenital nephrotic syndrome who develops nephrotic syndrome post transplantation, and also raises questions concerning the pathogenesis of congenital nephrotic syndrome.     

Levamisole therapy in corticosteroid-dependent nephrotic syndrome

The effect of prolonged treatment with levamisole was examined in 43 patients (30 boys) with steroid-dependent nephrotic syndrome (SDNS). The mean age at institution of treatment was 4.0±2.0 years. Fourteen patients had previously received cyclophosphamide with an ensuing remission of 8.5±10 months. Following induction of remission with prednisolone, levamisole was administered at a dose of 2.5 mg/kg body weight on alternate days. Prednisolone was tapered by 2.5 – 5 mg every 4 weeks to 0.5 mg/kg on alternate days. The duration of levamisole therapy ranged from 6 to 31 months (mean 17.4±8.4 months); 15 patients received levamisole for more than 18 months and 10 for more than 24 months. Prednisolone was discontinued in 18 patients after a mean duration of 11.7±7.1 months, whereas in 21 patients its dose was reduced to 0.2 – 0.4 mg/kg on alternate days. The mean relapse rate prior to levamisole therapy was 3.0±1.5 relapses/year, which reduced to 0.9±0.7 relapses/year during levamisole treatment (P <0.001). A comparison of the response in 14 patients who had previously received cyclophosphamide with the other 29 patients did not show any significant difference. There were no side effects of levamisole therapy. Our findings suggest that prolonged treatment with levamisole is beneficial and safe in SDNS, with a marked steroid-sparing effect. A significant proportion of these patients can be kept in remission on levamisole alone. Received March 26, 1996; received in revised form and accepted January 16, 1997     

The response to cyclophosphamide in steroid-sensitive nephrotic syndrome is influenced by polymorphic expression of glutathion-S-transferases-M1 and -P1

Glutathione-S-transferases (GST) play a central role in the inactivation of toxic drugs like cyclophosphamide (CP). These enzymes depict several polymorphisms with altered activity, and it has been shown that different polymorphisms influence the risk of malignancies and the outcome after chemotherapy. To prove the hypothesis that CP efficacy in children with nephrotic syndrome is influenced by polymorphic expression of GSTs, the genotype of 26 patients was analyzed and correlated with the outcome after CP treatment. All 26 children with steroid-sensitive nephrotic syndrome and frequent relapses or steroid dependency were treated with CP at a mean age of 6.7±4.0 years. CP was given in a dose of 2 mg/kg/day for 12±1 week. GST-M1, GST-P1 and GST-T1 polymorphisms were detected by PCR. In patients with GST-M1 null polymorphism, a significantly better rate of sustained remission was seen than in patients with the heterozygous or homozygous GST-M1 wildtype (0 versus 29%, P <0.01). In contrast, children with GST-P heterozygous or homozygous polymorphism had a significantly lower rate of sustained remission compared to homozygous wildtype (7 versus 38%, P <0.02). The GST-T1 genotype did not influence the outcome after CP treatment (P =0.32). Patients with the combination of GST-M1 null and GST-P1 wildtype did not relapse in 50%, compared to 6% in other children (P <0.01). We conclude that the polymorphic expression of GST-M1 and -P1 did significantly influence the long-term remission rate after CP treatment of steroid-sensitive nephrotic syndrome in children. Whereas GST-M1 null will increase cyclophosphamide efficacy, GST-P1 polymorphism seems to be related to enhanced susceptibility to further relapses.A part of this work was presented at the 31st meeting of the Arbeitsgemeinschaft Pädiatrische Nephrologie (APN), Vienna, Austria, 22–24 March 2001, and at the 12th congress of the International Pediatric Nephrology Association (IPNA), Seattle, Wash., 1–5 September 2001, and published in abstract form (Nieren- und Hochdruckkrankheiten 30:94, 2001, and Pediatric Nephrology 16:C123, 2001)     

Evaluation of chlorambucil therapy in steroid-dependent and cyclophosphamide-resistant children with nephrosis

A prospective study was performed to evaluate the efficacy of chlorambucil in inducing long-term remission in children with steroid-dependent or cyclophosphamide-resistant primary nephrotic syndrome (NS). The 15 steroid-dependent children had a relapse rate of 5.3/patient per year (range 4–8) and a mean age of 8.4 years (range 2–13). The chlorambucil dosage was 0.2 mg/kg per day for a total of 8 weeks. Nine patients (56%) remained in complete remission for an average of 39.2 months (range 16–70). The interval to the first relapse in the remaining 7 ranged from 4 to 41 months and the relapse rate decreased significantly to 0.6 relapses/patient per year (P<0.05). Five children had steroid- and cyclophosphamide-resistant NS, 4 with focal segmental glomerulosclerosis and 1 with mesangiol proliferative glomerulonephritis. Chlorambucil was given in a dose of 0.2 mg/kg per day for 8–16 weeks. Complete remission was obtained in 4 patients; 2 patients relapsed. No serious long-term complications were observed in our patients.     

Expression of glucocorticoid receptors in mononuclear cells in nephrotic syndrome

Coulter flow cytometry was used to determine glucocorticoid receptors (GCR) in the peripheral blood cells of patients with nephrotic syndrome. The expression of GCR in the lymphocytes (CD3/GCR) and monocytes (CD14/GCR) of peripheral blood of 23 (age 4.9±2.7 years) children with steroid-sensitive nephrotic syndrome was assessed before treatment (proteinuria >50 mg/kg per 24 h), after 4–6 weeks of prednisone treatment, without proteinuria, and in remission, without proteinuria and without any treatment. Before treatment the expression of CD3/GCR was 61.8±18.3% and CD14/GCR 43.6.8±20.3%; this did not differ from the results of the normal control group (P>0.05). However, after treatment GCR expression in lymphocytes was 50% (P<0.001) and in monocytes about 20% lower (P<0.05). In remission, the GCR expression increased and did not differ from the results before treatment (P>0.05). A positive correlation between the serum cortisol concentration and the expression of CD3/GCR was found (r=0.504, P=0.02). In summary, we report that in children with steroid-sensitive nephrotic syndrome, prednisone treatment causes the temporary decrease of the expression of GCR in lymphocytes. A positive correlation between GCR expression and serum cortisol was found. A decrease in GCR expression in monocytes did not correlate with cortisol concentration.